Research Goals: To examine putative protein markers of traumatic axonal injury (AI) in order to elucidate the neuropathology of mild traumatic brain injury (mild TBI) and its sequelae. Career Development Goals: To provide adequate time to mentor new clinical investigators and perform patient-oriented research in TBI. Research Project: Axonal injury is thought to be the pathophysiological process that underlies the cognitive and motor deficits found after mild TBI. The central hypothesis of this proposal is that axonal injury results in the differential expression of serum and cerebrospinal fluid (CSF) proteins and that examination of these proteins can provide insight into the mechanism of axonal injury. The goal of this project is to examine alterations in blood and CSF to test several hypotheses related to the biochemical and cellular response to mild TBI. This goal will be accomplished through two investigative strategies: 1) Analysis of the exposure characteristic of serum and CSF proteins; and 2) Correlation of protein markers of axonal damage to changes in axonal structure on diffusion tensor imaging (DTI) and cognitive function. Specifically, this project seeks to determine the putative role of a marker of neurofilament damage (pNFH) and a marker of lipid regulation (ApoA1) in axonal injury after mild TBI. The potential link between mild TBI and the increased long-term risk of neurodegeneration will be explored by an analysis of epigenetic changes in the DNA of circulating leukocytes. To address these aims the PIs propose to assemble a cohort of college athletes participating in contact sports in which mild TBI is a known risk, and a cohort of moderate to severe TBI patients who have an external ventriculostomy drain placed as a part of their clinical care. Because this study involves the investigation of several aspects of brain structure and function after mild, moderate and severe TBI, it serves as an ideal platform for the mentoring of new clinical investigators interested in traumatic brain injury. This proposal meets the goals of the K24 award by 1) demonstrating the need for the PI to devote more time to and to augment his research capabilities, and by 2) providing the ideal conditions under which new clinical investigators can be mentored in the conduct of Patient-Oriented Research. PUBLIC HEALTH RELEVANCE: Mild TBI is an important public health problem in the US for which there is currently no objective diagnostic aid and no treatment. This injury affects over 1.2 million Americans annually and is the signature injury of the conflicts in Iraq and Afghanistan. Mild TBI can result in problems of thinking and performing daily activities that can last from months to years. The process by which brain cells are damaged and how this damage is linked to brain dysfunction is incompletely understood. This has prevented the development of treatments that could improve the lives of those injured. The PIs propose to examine changes in the blood and spinal fluid to learn more about mild TBI. In the process they hope to train and inspire a new generation of clinical researchers interested in traumatic brain injury.